scholarly journals Distinct domains in Nbs1 regulate irradiation-induced checkpoints and apoptosis

2007 ◽  
Vol 204 (5) ◽  
pp. 1003-1011 ◽  
Author(s):  
Simone Difilippantonio ◽  
Arkady Celeste ◽  
Michael J. Kruhlak ◽  
Youngsoo Lee ◽  
Michael J. Difilippantonio ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Nijmegen Breakage Syndrome ◽  
Radiation Sensitivity ◽  
Terminal Region ◽  
Cell Cycle Checkpoint ◽  
Artificial Chromosomes ◽  
Downstream Target ◽  
Gonadal Dysfunction ◽  
Damage Response

The chromosomal instability syndromes Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT) share many overlapping phenotypes, including cancer predisposition, radiation sensitivity, cell-cycle checkpoint defects, immunodeficiency, and gonadal dysfunction. The NBS protein Nbs1 is not only a downstream target of AT mutated (ATM) kinase but also acts upstream, promoting optimal ATM activation, ATM recruitment to breaks, and ATM accessibility to substrates. By reconstituting Nbs1 knockout mice with bacterial artificial chromosomes, we have assessed the contribution of distinct regions of Nbs1 to the ATM-dependent DNA damage response. We find that T cell and oocyte development, as well as DNA damage-induced G2/M and S phase checkpoint arrest and radiation survival are dependent on the N-terminal forkhead-associated domain, but not on the principal residues phosphorylated by ATM (S278 and S343) or on the evolutionarily conserved C-terminal region of Nbs1. However, the C-terminal region regulates irradiation-induced apoptosis. These studies provide insight into the complex interplay between Nbs1 and ATM in the DNA damage response.

scholarly journals DNA-PKcs promotes chromatin decondensation to facilitate initiation of the DNA damage response

2019 ◽  
Vol 47 (18) ◽  
pp. 9467-9479 ◽  
Author(s):  
Huiming Lu ◽  
Janapriya Saha ◽  
Pauline J Beckmann ◽  
Eric A Hendrickson ◽  
Anthony J Davis
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Cellular Response ◽  
Kinase Activity ◽  
Human Cell Line ◽  
Cell Cycle Checkpoint ◽  
Chromatin Decondensation ◽  
Damage Site ◽  
Damage Response

Abstract The DNA damage response (DDR) encompasses the cellular response to DNA double-stranded breaks (DSBs), and includes recognition of the DSB, recruitment of numerous factors to the DNA damage site, initiation of signaling cascades, chromatin remodeling, cell-cycle checkpoint activation, and repair of the DSB. Key drivers of the DDR are multiple members of the phosphatidylinositol 3-kinase-related kinase family, including ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related (ATR), and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). ATM and ATR modulate multiple portions of the DDR, but DNA-PKcs is believed to primarily function in the DSB repair pathway, non-homologous end joining. Utilizing a human cell line in which the kinase domain of DNA-PKcs is inactivated, we show here that DNA-PKcs kinase activity is required for the cellular response to DSBs immediately after their induction. Specifically, DNA-PKcs kinase activity initiates phosphorylation of the chromatin factors H2AX and KAP1 following ionizing radiation exposure and drives local chromatin decondensation near the DSB site. Furthermore, loss of DNA-PKcs kinase activity results in a marked decrease in the recruitment of numerous members of the DDR machinery to DSBs. Collectively, these results provide clear evidence that DNA-PKcs activity is pivotal for the initiation of the DDR.

scholarly journals The RNA polymerase I transcription inhibitor CX-5461 cooperates with topoisomerase 1 inhibition by enhancing the DNA damage response in homologous recombination-proficient high-grade serous ovarian cancer

2020 ◽  
Author(s):  
Shunfei Yan ◽  
Jiachen Xuan ◽  
Natalie Brajanovski ◽  
Madeleine R. C. Tancock ◽  
Piyush B. Madhamshettiwar ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Homologous Recombination ◽  
Dna Damage Response ◽  
Cell Cycle Checkpoint ◽  
Common Mechanism ◽  
High Grade ◽  
M Cell ◽  
Topoisomerase 1 ◽  
Damage Response

Abstract Background Intrinsic and acquired drug resistance represent fundamental barriers to the cure of high-grade serous ovarian carcinoma (HGSC), the most common histological subtype accounting for the majority of ovarian cancer deaths. Defects in homologous recombination (HR) DNA repair are key determinants of sensitivity to chemotherapy and poly-ADP ribose polymerase inhibitors. Restoration of HR is a common mechanism of acquired resistance that results in patient mortality, highlighting the need to identify new therapies targeting HR-proficient disease. We have shown promise for CX-5461, a cancer therapeutic in early phase clinical trials, in treating HR-deficient HGSC. Methods Herein, we screen the whole protein-coding genome to identify potential targets whose depletion cooperates with CX-5461 in HR-proficient HGSC. Results We demonstrate robust proliferation inhibition in cells depleted of DNA topoisomerase 1 (TOP1). Combining the clinically used TOP1 inhibitor topotecan with CX-5461 potentiates a G2/M cell cycle checkpoint arrest in multiple HR-proficient HGSC cell lines. The combination enhances a nucleolar DNA damage response and global replication stress without increasing DNA strand breakage, significantly reducing clonogenic survival and tumour growth in vivo. Conclusions Our findings highlight the possibility of exploiting TOP1 inhibition to be combined with CX-5461 as a non-genotoxic approach in targeting HR-proficient HGSC.

ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response

Nature ◽  
2000 ◽  
Vol 405 (6785) ◽  
pp. 477-482 ◽  
Author(s):  
Xiaohua Wu ◽  
Velvizhi Ranganathan ◽  
David S. Weisman ◽  
Walter F. Heine ◽  
David N. Ciccone ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Nijmegen Breakage Syndrome ◽  
Damage Response ◽  
Syndrome Protein

scholarly journals Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3415
Author(s):  
Peter H. Goff ◽  
Rashmi Bhakuni ◽  
Thomas Pulliam ◽  
Jung Hyun Lee ◽  
Evan T. Hall ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Tumor Immunity ◽  
Immune Checkpoint ◽  
Ataxia Telangiectasia ◽  
Management Strategies ◽  
Adaptive Immune Response ◽  
Cell Cycle Checkpoint ◽  
Damage Response ◽  
Cycle Checkpoint

Metastatic cancers resistant to immunotherapy require novel management strategies. DNA damage response (DDR) proteins, including ATR (ataxia telangiectasia and Rad3-related), ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), have been promising therapeutic targets for decades. Specific, potent DDR inhibitors (DDRi) recently entered clinical trials. Surprisingly, preclinical studies have now indicated that DDRi may stimulate anti-tumor immunity to augment immunotherapy. The mechanisms governing how DDRi could promote anti-tumor immunity are not well understood; however, early evidence suggests that they can potentiate immunogenic cell death to recruit and activate antigen-presenting cells to prime an adaptive immune response. Merkel cell carcinoma (MCC) is well suited to test these concepts. It is inherently immunogenic as ~50% of patients with advanced MCC persistently benefit from immunotherapy, making MCC one of the most responsive solid tumors. As is typical of neuroendocrine cancers, dysfunction of p53 and Rb with upregulation of Myc leads to the very rapid growth of MCC. This suggests high replication stress and susceptibility to DDRi and DNA-damaging agents. Indeed, MCC tumors are particularly radiosensitive. Given its inherent immunogenicity, cell cycle checkpoint deficiencies and sensitivity to DNA damage, MCC may be ideal for testing whether targeting the intersection of the DDR checkpoint and the immune checkpoint could help patients with immunotherapy-refractory cancers.

scholarly journals Arabidopsis Casein Kinase 2 triggers Stem Cell Exhaustion under Al Toxicity and Phosphate Deficiency Through activation of the DNA Damage Response pathway

2020 ◽  
Author(s):  
Wei Pengliang ◽  
Manon Demulder ◽  
Pascale David ◽  
Thomas Eekhout ◽  
Kaoru Okamoto Yoshiyama ◽  
...  
Keyword(s):  
Dna Damage ◽  
Stem Cell ◽  
Dna Damage Response ◽  
Stem Cell Niche ◽  
Al Toxicity ◽  
Cell Cycle Checkpoint ◽  
Damage Response ◽  
Cycle Checkpoint ◽  
Cell Niche ◽  
Dna Damage Response Pathway

Aluminum (Al) toxicity and inorganic phosphate (Pi) limitation are widespread chronic abiotic and mutually enhancing stresses that profoundly affect crop yield. Both stresses cause a strong inhibition of root growth, resulting from a progressive exhaustion of the stem cell niche. Here, we report on a casein kinase 2 (CK2) inhibitor identified by its capability to maintain a functional root stem cell niche under Al toxic conditions. CK2 operates through phosphorylation of the cell cycle checkpoint activator SUPPRESSOR OF GAMMA RADIATION1 (SOG1), priming its activity under DNA-damaging conditions. In addition to yielding Al tolerance, CK2 and SOG1 inactivation prevents meristem exhaustion under Pi starvation, revealing the existence of a low Pi-induced cell cycle checkpoint that depends on the DNA damage activator ATAXIA-TELANGIECTASIA MUTATED. Overall, our data reveal an important physiological role for the plant DNA damage response pathway under agriculturally limiting growth conditions, opening new avenues to cope with Pi limitation.

scholarly journals Exploring the Involvement of FoxM1 in CML Cells from DNA Damage Response-Regulatory Prospective

2021 ◽  
Author(s):  
Lin Du ◽  
Manli Wang ◽  
Hui Li ◽  
Fang Wang
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Repair System ◽  
Downstream Target ◽  
Damage Repair ◽  
Healthy Donors ◽  
Damage Response ◽  
M Phase ◽  
The Status

Abstract Background FoxM1 is widely accepted as an oncogenesis factor, for it is one of the most frequently upregulated genes in a broad spectrum of human malignancies. Herein, we presented the status of FoxM1 in CML samples and cell lines. Methods We compared FoxM1 abundance and phosphorylation using PB-MNC samples from CML patients and healthy donors. DNA damage response (DDR) was investigated in the presence of oncogene or chemical. Through enforced expression of FoxM1 or lentivirus mediated silencing, we explored the participation of FoxM1 in DDR regulation. Results Overexpression of FoxM1 was only observed in 3 samples from patients of advanced stage. However, hyper-phosphorylation of FoxM1 was evidently detected in the CML cohort. Furtherly, the DNA damage response that in accompany with the formation of Bcr/Abl was responsible for the rise in FoxM1 phosphorylation. Bcr/Abl provoked a modest extent of DNA damage, which, in turn, roused the repair system, mirrored by phosphorylation of the ATM/ATR-CHK1/2 axis. FoxM1 was a downstream target of CHK1 which directly associated with FoxM1 in the presence of DNA damage. Activation of FoxM1 served as a DDR regulator by inducing the expression of Rad51 and Brca1, genes that participated in DNA repair. Depletion of FoxM1 impaired DNA repair, leading to cell cycle arrest in G2/M phase and the onset of apoptosis in a P53-dependent fashion. Finally, our data demonstrated that phosphorylation of FoxM1 did not rely on Bcr/Abl kinase activity. Suppression of FoxM1 showed lethal potential to primary CML cells, and most importantly, the lethality was not affected by the TKIs insensitiveness. Conclusions Abnormality in FoxM1 activity in CML cells enlightened us that constantly present DNA damage rendered leukemia cells more reliant upon the DNA damage repair system. Targeting FoxM1 could be exploit as an alternative strategy to overcome TKIs resistance.

An intimate alliance of DNA-damage response network with cell-cycle checkpoints amid events of uncontrolled cellular proliferation- a minireview

2020 ◽  
Vol 20 ◽  
Author(s):  
Aroni Chatterjee ◽  
Keshav Rajarshi ◽  
Rajni Khan ◽  
Hiya Ghosh ◽  
Sonia Kapoor ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Cellular Proliferation ◽  
Cell Senescence ◽  
Cell Cycle Checkpoint ◽  
Effector Proteins ◽  
Cell Cycle Checkpoints ◽  
Response Network ◽  
Damage Response

: There is close interdependence between cell survival, cell senescence, events of the cell cycle, apoptosis, malignancy development, and tumor responses to cancer treatment. Intensive studies and elaborate researches have been conducted on the functional aspects of oncogenes, tumor suppressor genes, apoptotic genes, and members guiding cell cycle regulation. These disquisitions have put forward the existence of a highly organized response pathway termed as a DNAdamage response network. The pathways detecting DNA damage and signaling are intensively linked to the events of cellcycle arrest, cell proliferation, apoptosis, and cell senescence. DNA damage responses are complex systems that incorporate specific "sensor" and "transducer" proteins, for assessment of damage and signal transmission, respectively. These signals are thereafter relayed upon various "effector" proteins involved in different cellular pathways. It may include those governing cell-cycle checkpoints, participating in DNA repair, cell senescence, and apoptosis. This review discusses about the role of tumour suppressor gene, oncogenes, cell cycle checkpoint regulators during DNA damage response and regulation.

Sign in / Sign up

Export Citation Format

Share Document